The following discussion of the background is merely provided to aid the reader in understanding the invention and is not admitted to describe or constitute prior art to the invention.
In mammalian cells, there are two types of phosphatidylinositol phosphate kinases: Type I and Type II. Both types serve to produce various phosphoinositides, phospholipid second messengers which are important in a variety of cellular functions ranging from cell motility to focal adhesion assembly to protein trafficking. Type I phosphatidylinositol phosphate kinase (“PIPKI”) exists in at least three isoforms—α, β, and γ. These isoforms are the major producers of a second messenger named phosphatidylinositol-4,5-bisphosphate (“PI4,5P2”). PI4,5P2 is a membrane phospholipid which plays a role in many cellular signaling pathways. Even though PI4,5P2 is maintained at relatively constant levels in cells, it is hypothesized that small local changes in the spatial and temporal synthesis of PI4,5P2 defines its role as a second messenger.
The different PIPKI isoforms are differentially expressed spatially and temporally, thereby providing a mechanism for control of PI4,5P2 generation. The C-termini of the PIPKIs are sequence divergent, indicating that this region may be important for functional divergence. Further, each type I PIP kinase isoform mRNA transcript may be alternatively spliced, thereby resulting in multiple splice variants, each differentially localized for specific cellular functions. Thus, the distinct localization and targeting of these different kinase isoforms allows for PI4,5P2 production at specific sites throughout the cell, resulting in spatial and temporal regulation of multiple cellular processes. Such localization may be facilitated by the interaction of the PIP kinases with protein partners capable of targeting the kinase to specific sub-cellular compartments. Interestingly, many of these protein partners are themselves PI4,5P2 effectors.
Accordingly, the identification and characterization of novel PIP kinases which affect the expression levels or localization of second messengers such as PI4,5P2 would be an important step in further elucidating phosphatidylinositol based signaling pathways. Here, two novel human PIPKIγ splice variants, termed PIPKIγ 700 and PIPKIγ 707, are described.